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  • 1. Hypertension, Renal Disease, and Drug Considerations Domenic A. Sica, MD Chairman Division of Clinical Pharmacology and Hypertension Division of Nephrology Professor of Medicine and Pharmacology Virginia Commonwealth University Health Systems Richmond, Virginia
  • 2. Projections for the Year 2010: Incident & Point-Prevalent ESRD Patients 700 661,330 Number of Patients 600 Projection Number of Patients, 95% Confidence Interval 500 Point thousands prevalence 400 R2 = 99.7% 372,407 300 200 326,217 172,667 98,953 86,825 100 Incidence R2 = 99.8% 0 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 USRDS 2000 Annual Data Report. Bethesda, Md. 2000.
  • 3. Adjusted ESRD Incident Rates, by Primary Diagnosis and Diabetes in the General Population Prevalence of Diabetes Incident Rates in the ESRD Population in the General Population 350 9 Glomerulonephritis Rate per Million Population 300 Percent of Population Cystic Kidney 8 250 All 200 Diabetes 7 Hypertension 150 6 100 5 50 0 4 81 83 85 87 89 91 93 95 97 99 01 90 91 92 93 94 95 96 97 98 99 00 01 Incident ESRD patients; rates adjusted for age, gender, & race. Data on the prevalence of diabetes in the general population obtained from the CDC’s Behavioral Risk Factor Surveillance System. United States Renal Data Sytem. 2003 Annual Data Report Graphics. Available at: http://www.usrds.org/slides.htm. Accessed 31 October 2003.
  • 4. CVD Mortality Markedly Increased in ESRD • CVD mortality 10–20 times higher in ESRD than the general population • 120 times higher for ESRD patients aged 25 to 34 100 Dialysis male Annual Mortality, % 10 Dialysis female Dialysis black 1 Dialysis white 0.1 GP male GP female 0.01 GP black GP white 25–34 35–44 45–54 55–64 65–74 75–84 >85 GP = General population. Age, years Reprinted with permission from Foley RN et al. Am J Kidney Dis. 1998;32(suppl 3):S112–S119.
  • 5. All-Cause Mortality in the General Medicare and Dialysis Populations (Pts Age 65+) 400 CVD 350 No CVD 300 250 Deaths/1000 pt-yr at risk 200 150 100 50 0 Non-CKD CKD Dialysis
  • 6. Stages of CKD and CVD ESRD End- CHF Stage CRI ( GFR) ASCVD Progression events Albuminuria CAD Initiation Proteinuria LVH Elderly, DM, “At Risk” Elderly, DM, HBP HBP CKD CVD Sarnak MJ, Levey AS. Am J Kidney Dis. 2000;35:S117-S131.
  • 7. Stages of Chronic Kidney Disease: NKF K/DOQI Classification GFR (mL/min/1.73 m2) 130 90 60 30 15 0 Stage I Stage II Stage III Stage IV Stage V CKD risk Mild Moderate Severe Kidney factors/damage kidney kidney kidney failure, with preserved function function function ESRD GFR Risk of RCN, dialysis, and death Prevalence 5.8% 12.3% 4.3% 0.2% 0.1% n (x1000) 10,259 21,794 7,553 363 300 CKD=chronic kidney disease, ESRD=end-stage renal disease, GFR=glomerular filtration rate, NKF K/DOQI=National Kidney Foundation Kidney Disease Outcomes Quality Initiative, RCN=radiocontrast nephropathy Adapted from National Kidney Foundation. Am J Kidney Dis. 2002;39(2suppl 2):S1-S246.
  • 8. Serum creatinine and GFR relationship Cut point for drug accumulation Creatinine clearance
  • 9. What Is Known  Specific indications for agents blocking the renin- angiotensin-aldosterone system (RAAS): – Chronic kidney disease with proteinuria – Congestive heart failure  Equivalence of classes for most other outcomes  Need for adequate diuresis or sodium restriction  Safety of calcium channel blockers for both cardiac and renal outcomes.  Need for multiple agents for most patients
  • 10. Long-term Decline in GFR is Correlated With Poor Control of Blood Pressure: 9 Studies on Nephropathy Progression MAP (mmHg) 95 97 99 101 103 105 107 109 111 113 115 117 119 121 0 (ml/min/yr) (mmHg) –2 –4 GFR –6 –8 –10 Untreated HTN –12 –14 130/85 140/90 *Trials marked by * are non-diabetic renal disease patients. Graph: (Bakris GL. J Clin Hypertens. 1999) Trials: (Parving HH, et al. Br Med J. 1989) (Viberti GC, et al. JAMA. 1993) (Klaur S, et al. N Engl J Med. 1993*) (Herbert L, et al. Kidney Int. 1994) (Lebovitz H, et al. Kidney Int. 1994) (Moschio G, et al. N Engl J Med. 1996*) (Bakris GL, et al. Kidney Int. 1996) (Bakris GL, et al. Hypertension. 1997) (GISEN Group, Lancet. 1997)
  • 11. The Need for Sodium Restriction or Adequate Diuresis • Most classes of antihypertensive agents lead, by compensation for lower BP, to sodium retention. This may substantially blunt the anti-hypertensive effect • JNC 7 recommends that “most patients should receive a regimen including a thiazide type diuretic, either alone or with other agents.” • This is particularly important in patients with high sodium intakes, in particular African-American patients. In African- Americans, adequate diuresis restores a responsiveness to RAAS blockers similar to that in Caucasians
  • 12. Rationale for Combination of an ACE inhibitor of an ARB With a Diuretic Diuretic Effects JG Cells Renin Angiotensin I Renin Volume Release Depletion Angiotensin II ARB AT1 Receptor Distal Tubule Na+ Diuresis Vasoconstriction Less Na+ Reabsorbed
  • 13. Safety of Calcium Channel Blockers  Concern has been expressed in the past about the safety of CCBs with respect to both cardiac and renal outcomes  The ALLHAT found amlodipine to be equivalent to chlorthalidone and lisinopril in cardiac outcomes  The IDNT in a randomized comparison found no beneficial or adverse impact of amlodipine (other than BP reduction) on renal outcomes or proteinuria  The RENAAL in a secondary analysis found no beneficial or adverse impact on renal outcomes of use of any CCBs
  • 14. Angiotensin II and Diabetic Renal Disease Afferent 3. Abnormal matrix metabolism: arteriole 1. Deficient decrease autoregulation: angiotensin II control of systemic modulation arterial pressure Glomerulus Bowman’s capsule Efferent arteriole 2. Increased efferent resistance: decrease intrarenal angiotensin II effect
  • 15. Renin-Angiotensin System Angiotensinogen (-) Renin Angiotensin I Bradykinin Non-renin Non-ACE ACE Angiotensin II Inactive kinins BP AT1 AT2 • Vasoconstriction • Vasodilation • Aldosterone secretion • Inhibition of cell growth • Catecholamine release • Cell differentiation • Proliferation • Injury response • Hypertrophy • Apoptosis Ellis ML et al. Pharmacotherapy. 1996;16:849-860. Carey RM et al. Hypertension. 2000;35:155-163.
  • 16. ACEIs and ARBs in Chronic Renal Failure Renal and Pharmacokinetic Differences Parameter ACEIs ARBs Proteinuria Uric acid * Glomerular filtration rate Hyperkalemia Dose titration suggested Yes No BP reduction Systemic accumulation Yes No AT2 receptor stimulation * Occurs only with losartan
  • 17. What Is Not Yet Known  Appropriate doses of ACEIs or ARBs in proteinuric kidney disease and CHF, and how to target the optimal doses  Benefits of combining ACEIs and ARBs in proteinuric kidney disease and CHF  Appropriate BP targets (<140 mm Hg) in patients with proteinuric and non-proteinuric kidney disease  Appropriate BP targets (<140 mm Hg) for optimal vascular (CAD and stroke) outcomes
  • 18. Dosing of RAAS Blockers for Renal Protection  The currently established dose ranges for all ACEIs and ARBs were based on maximum BP reduction  There is no reason to assume that the maximal dose for BP control will also be the appropriate dose for renal protection (or protection against CHF)  It is unlikely that trials such as the IDNT or RENAAL, with hard clinical end points, will be undertaken to establish the optimal doses of these agents.
  • 19. Dose–Response and Antiproteinuric Relationship for an ACE inhibitor or an Angiotensin-receptor blocker Dose–Therapeutic 100 Response Relationship Dose–Adverse Maximum Tolerated Response Relationship Effect, % Adverse Effect Minimum Useful Effect Therapeutic Range 0 Dose
  • 20. Characteristics of ACE Inhibitors  Dosing – Once daily versus multiple – Variable trough-to-peak ratios  Pharmacokinetics – Terminal elimination phase – Route of elimination » Renal or renal/hepatic  Physical characteristics* – Lipophilicity – Plasma ACE or plasma/tissue ACE binding  Ethnicity – Some have been studied to have documented differential effects in black patients *The clinical significance of tissue ACE inhibition has not been established in humans.
  • 21. Inhibiting ACE at Two RAS Sites: Circulation and Tissue Circulating ACE Tissue ACE 10% of ACE 90% of ACE Angiotensin I Angiotensin I ACE ACE Inhibition ACE Angiotensin II Angiotensin II Degrades Bradykinin Peripheral Negative Feedback Vasoconstriction on Renin Secretion Bradykinin Stimulates Aldosterone Stimulates Stimulates Secretion Nitric Oxide Prostaglandin (NO) Release ACE = angiotensin-converting enzyme; Vasodilator RAS = renin-angiotensin system. Growth Inhibitor Kang PM et al. Am Heart J. 1994;127:1388-1401. Antiatherogenic Antithrombotic Gibbons GH. Am J Cardiol. 1997;79:3-8. Anti-inflammatory Dzau VJ. Arch Intern Med. 1993;153:937-942. Antioxidant
  • 22. Pharmacology of Angiotensin Receptor Blockers Half-Life Bioavailability Volume of % Renal/Hepatic Drug (h) (%) Distribution Clearance Candesartan 9 15 0.13 L/kg 60/40 Eprosartan 5 13 13 L 30/70 Irbesartan 11-15 60-80 53-93 L 1/99 Losartan 2 33 34 L 10/90 E-3174 6-9 – 12 L 50/50 Olmesartan 10-15 28 17 L 45/55 Telmisartan 24 42-58 500 L 1/99 Valsartan 6 25 17 L 30/70
  • 23. What Is Not Yet Known  Appropriate doses of ACEIs or ARBs in proteinuric kidney disease and CHF, and how to target the optimal doses  Benefits of combining ACEIs and ARBs in proteinuric kidney disease and CHF  Appropriate BP targets (<140 mm Hg) in patients with proteinuric and non-proteinuric kidney disease  Appropriate BP targets (<140 mm Hg) for optimal vascular (CAD and stroke) outcomes
  • 24. Angiotensin Receptor Blocker and ACE Inhibitor Combination Therapy PRINCIPLES  Pharmacokinetic considerations  Sequence effect  Dose-response relationships  Time of day of dosing  Point-in-time for assessment of additive response and parameters measured
  • 25. COOPERATE: Study Design Design: Randomized, double-blind trial in 263 patients with nondiabetic renal disease Primary Composite of time to doubling of serum Endpoint: creatinine concentration or ESRD Randomization: Losartan 100 mg/day + AHT* as needed Trandolapril 3 mg/day + AHT* as needed Duration: 3 yrs Target BP: SBP <130 mmHg DBP <80 mmHg *Antihypertensive therapy (excluding other ACEIs or other ARBs). Nakao N et al. Lancet. 2003;361:117–124.
  • 26. COOPERATE: UAER 3 Trandolapril Losartan Median Urinary Protein Combination Excretion, g/day 2 1 0 0 5 10 15 20 25 30 35 40 Months After Randomization Baseline Reprinted with permission from Nakao N et al. Lancet. 2003;361:117–124.
  • 27. COOPERATE: Primary Endpoint Doubling of Serum Creatinine or Progression to ESRD 30 Trandolapril Losartan Proportion Reaching 25 Combination Endpoint, % 20 15 10 5 P = 0.02 0 0 5 12 18 24 30 36 Number at Risk Months After Randomization Losartan 89 88 84 79 65 59 47 Trandolapril 86 85 83 75 72 63 58 Combination 88 87 86 83 76 73 67 Reprinted with permission from Nakao N et al. Lancet. 2003;361:117–124.
  • 28. What Is Not Yet Known  Appropriate doses of ACEIs or ARBs in proteinuric kidney disease and CHF, and how to target the optimal doses  Benefits of combining ACEIs and ARBs in proteinuric kidney disease and CHF  Appropriate BP targets (<140 mm Hg) in patients with proteinuric and non-proteinuric kidney disease  Appropriate BP targets (<140 mm Hg) for optimal vascular (CAD and stroke) outcomes
  • 29. AASK Enrollment 2801 Screened 1094 Randomized 441 436 Randomized to receive ramipril 217 Randomized to receive amlodipine Randomized to 3 Did not receive ramipril receive 6 Did not receive amlodipine 433 Received ramipril as assigned metoprolol 211 Received amlodipine as assigned 20 No follow-up GFR 7 No follow-up GFR 50 No GFR in final year of follow-up 23 No GFR in final year of follow-up 0 Withdrawn Ongoing 0 Withdrawn 47 Dialysis 32 Dialysis 18 Death 13 Death 321 Active participants 149 Active participants AASK Study Group. JAMA. 2001;285:2719–2728.
  • 30. AASK: Risk Reduction in GFR Decline*, ESRD, or Death With ACEI, -Blockade, or CCB 0 –10 –22% –19% % –20 Metoprolol vs Risk Ramipril vs amlodipine Reduction –30 metoprolol P=.19 –38% P=.005 –37% –40 Metoprolol vs Ramipril vs –16% amlodipine amlodipine P=.003 –50 P=.042 Ramipril vs amlodipine P=.004 Patients with existing kidney damage (baseline UP/C <0.22) *Decrease from baseline GFR of 50%, or 25 mL/min/1.73 m2. Agodoa LY et al. JAMA. 2001;285:2719–2728.
  • 31. AASK: Blood Pressure Results  Patients randomized to standard vs aggressive BP lowering – Standard target: 140/90 mm Hg – Aggressive target: 125/75 mm Hg  Findings underscore importance of BP control even in patients with minimal renal dysfunction  Aggressive BP lowering beyond usual levels did not further slow renal disease progression Wright JT et al. Arch Intern Med. 2002;162:1636–1643. Wright JT et al. JAMA. 2002;288:2421–2431.
  • 32. What Is Not Yet Known  Appropriate doses of ACEIs or ARBs in proteinuric kidney disease and CHF, and how to target the optimal doses  Benefits of combining ACEIs and ARBs in proteinuric kidney disease and CHF  Appropriate BP targets (<140 mm Hg) in patients with proteinuric and non-proteinuric kidney disease  Appropriate BP targets (<140 mm Hg) for optimal vascular (CAD and stroke) outcomes
  • 33. CVD Risk Factors in CKD  Hypertension  Diabetes/metabolic syndrome  Dyslipidemia  Inflammation  Endothelial dysfunction  Hyperhomocysteinemia  Hyperparathyroidism – Ca2+/PO4  Uric acid elevations  Anemia  LVH  Smoking  Physical inactivity  Sleep apnea
  • 34. Target Blood Pressure For Individuals With: BP Goal: Hypertension <140/90 mmHg (no diabetes or renal disease) (JNC 7) Diabetes Mellitus <130/80 mmHg (ADA, JNC 7) Renal Disease <135/85 mmHg with proteinuria >1 gram/24 hours <125/75 mmHg or diabetic kidney disease (NKF) Chobanian AV et al. JAMA. 2003;289:2560–2571. American Diabetes Association. Diabetes Care. 2002;25:134–147. National Kidney Foundatrion. Am J Kidn Dis. 2002;39(suppl 1):S1–S266.
  • 35. Case Study No. 2: Teaching Points  What’s the role of diuretic therapy in the management of this patient’s HTN?  How do ACEs/ARBs fit into this patient’s management?  After initiation of pharmacotherapy, lab tests show a rise in serum Cr to 5.0 mg/dL. What is the next therapeutic step?  Despite maximum titrated doses of ACE/ARB, symptoms do not resolve. What additional management strategies should be considered?  The patient develops angioneurotic edema while taking an ACE inhibitor. What is the next therapeutic step?  Disease progression leads to refractory edema. What management steps should be considered to overcome his diuretic resistance?

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